THE EFFECTS OF N-ACETYLCYSTEINE AND ANTI-INTERCELLULAR ADHESION MOLECULE-1 MONOCLONAL-ANTIBODY AGAINST ISCHEMIA-REPERFUSION INJURY OF THE RAT STEATOTIC LIVER PRODUCED BY A CHOLINE-METHIONINE-DEFICIENT DIET

Abundant fat in the liver has been implicated in poor out-come after l iver transplantation or liver surgery, but the reasons for this associ ation are still unclear, The aim of the present study was to examine m echanisms that may be involved in hepatic dysfunction after ischemia-r eperfusion (I/R) of the steatotic rat liver, Steatosis was produced by a choline-methionine-deficient (CMDD) diet, In the first experiment, isolated perfused rat livers, subjected to 24-hour cold storage follow ed by 120-minute reperfusion, were used To investigate hypothermic I/R injury of the steatotic rat liver, In the second experiment, livers w ere subjected to 60-minute partial. left lobar vascular clamping to al low study of normothermic I/R injury. In the first experiment, compare d with normal non-steatotic liver, steatotic livers showed significant ly greater injury, as assessed by amounts of hepatic enzymes released into the perfusate, bile production, the concentrations of reduced glu tathione (GSH) in the perfusate, as well as in the livers themselves, and electron microscopic findings of sinusoidal microcirculatory injur y. The addition of N-acetylcysteine (NAC), a precursor of glutathione, to the liver before cold storage significantly improved these paramet ers in steatotic livers. The second experiment showed that, compared w ith nonsteatotic livers, steatotic livers had lower concentrations of GSH and impaired rates of bile production. There was also evidence of increased oxidative stress in polymorphonuclear leukocytes (PMNLs) in liver or peripheral blood of rats with fatty livers, An anti-rat inter cellular adhesion molecule-1 (ICAM-1) monoclonal antibody inhibited ne utrophil infiltration into pericentral sinusoids and improved these pa rameters in the steatotic rats, We conclude that sinusoidal microcircu latory injury is involved in hypothermic I/R injury, that oxidative st ress produced by PMNLs is involved in normothermic I/R injury, and tha t NAC and anti-rat ICAM-1 monoclonal antibody restore liver integrity in I/R injury.